ABSTRACT Close to a million people are addicted to or have abused cocaine according to current statistics. Moreover, there is an extremely high rate of relapse to cocaine use even after several months of abstinence. No medications are clinically available to treat cocaine addiction. Preclinical studies including our preliminary data, indicate that dopamine receptor targeting strategies that feature D1 partial agonism are promising for anti-cocaine medications development. In that regard, compounds that exhibit selective D1 partial agonism have demonstrated efficacy in cocaine self-administration and reinstatement behavioral paradigms in animals. However, the available selective D1 partial agonists suffer from poor pharmacokinetic properties (including oral bioavailability and blood-brain barrier penetrability) which precludes their clinical translation. The tetrahydroprotoberberine (THPB) chemotype is a novel scaffold from which to mine selective D1 partial agonists. In this proposal, we will solve the critical need for clinically useful D1 partial agonists by deploying strategic chemical modifications on the THPB lead compounds identified from our preliminary studies via parallel optimization of pharmacokinetic properties and D1 partial agonist pharmacologies. The long term goal of this proposal is to use the THPB framework to develop novel, bioavailable, selective D1 partial agonists for the treatment of cocaine addiction. We will test the central hypothesis that The THPB framework may be structurally manipulated to afford novel, bioavailable and selective D1 partial agonists with the ability to reduce cocaine craving in rats . Testing this hypothesis will engage three specific aims entailing synthesis, in vitro testing and in vivo behavioral assays. In the first specific aim, we will synthesize libraries of THPB analogues that contain bioisosteric replacements for metabolically labile functional groups in the lead THPBs, HUN4404 and HUN361. Specific Aim 2 will involve assessment of in vitro ADME properties as well as affinities and functional activities of the ligands at dopamine receptors via a variety of well-established assays for such. In Aim 3, compounds from Aim 2 that meet defined criteria for dopamine receptor activity and in vitro ADME properties will be submitted to an in vivo PK screen. Subsequently, selected compounds will be evaluated in a battery of behavioral assays relevant to cocaine addiction viz. self-administration and cocaine reinstatement. We expect to uncover novel D1 partial agonists that will be transformative in the field as novel in vivo tools and experimental anti-cocaine therapeutics.